Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models.
Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models.
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DOI：
10.1158/0008-5472.can-14-3167
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发表时间：
2015-06-15
期刊：
影响因子：
11.2
通讯作者：
Cross DA
中科院分区：
文献类型：
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作者：
Eberlein CA;Stetson D;Markovets AA;Al-Kadhimi KJ;Lai Z;Fisher PR;Meador CB;Spitzler P;Ichihara E;Ross SJ;Ahdesmaki MJ;Ahmed A;Ratcliffe LE;O'Brien EL;Barnes CH;Brown H;Smith PD;Dry JR;Beran G;Thress KS;Dougherty B;Pao W;Cross DA
对靶向EGFR抑制剂的耐药性可能在EGFR突变型肺癌中发展。早期鉴定对这些药物的先天性或获得性耐药机制对于指导未来疗法的开发至关重要。我们描述了对当前和新开发的EGFR TKI（包括AZD 9291）获得性耐药的EGFR突变细胞（PC 9和/或NCI-H1975）群体中异质性耐药机制的检测。我们报告了在对吉非替尼、阿法替尼、WZ 4002或AZD 9291耐药的细胞群中检测到NRAS突变，包括一种新型E63 K突变，以及WT NRAS或WT KRAS拷贝数增加。与亲本细胞相比，当与原始EGFR抑制剂联合治疗时，许多耐药细胞群对MEK抑制剂司美替尼（AZD 6244; ARRY-142886）的抑制作用更敏感。在体外，AZD 9291与司美替尼的组合防止了PC 9细胞中耐药性的出现，并延迟了NCI-H1975细胞中的耐药性。在体内，AZD 9291与司美替尼联合给药导致EGFRm/T790 M转基因模型中的AZD 9291耐药肿瘤消退。我们的数据支持使用AZD 9291与MEK抑制剂的组合来延迟或预防EGFRm和/或EGFRm/T790 M肿瘤对AZD 9291的耐药性。此外，这些研究结果表明，来自使用当前或开发中的EGFR抑制剂进展的患者的肿瘤样本中的NRAS修饰可能支持EGFR和MEK抑制剂组合的后续治疗。
Resistance to targeted EGFR inhibitors is likely to develop in EGFR mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR TKIs including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002 or AZD9291. Compared to parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumours in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumours. Further, these findings suggest that NRAS modifications in tumour samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.